This project is centered on the insulin-like growth factor type I receptor (IGF-IR), and its ability to stimulate cellular proliferation and transformation. It is based on substantial evidence that an overexpressed IGF-IR is transforming, while on the contrary, a decreased expression leads to reversal of the transformed phenotype in several cell types. The project will endeavor: 1) to establish unequivocally the domains of the IGF-IR that are necessary for mitogenesis and transformation (by mutational analysis); 2) to identify the substrates that transmit the mitogenic and transforming signals of the IGF-IR including Grb10, already identified as a new substrate; and 3) to determine the importance of quantitative changes in the expression of the IGF-IR in the control of cell proliferation: 4) to explore possible mechanisms of action of IGF-II in mitogenesis. The findings of their laboratory that mitogenesis and transformation can be dissociated at a molecular level, and that several strategies against the IGF-1R RNA inhibit transformation and tumorigenesis clearly point out the relevance of these studies to the cancer problem, both from a basic point of view and from a practical point of view.